Orthopedics is a branch of surgery dealing with fixation, repairing or reconstruction of damaged bones, also applied in fields such as traumatology, neurosurgery and maxillo-facial surgery.
A technique commonly used in orthopedics is the insertion of implants in the body for the fixation or reconstruction of bones and their parts. Implants are generally made of biocompatible metals (in particular titanium, cobalt-chrome, etc.), polymers, ceramics, hydroxyapatite, or their combinations (e.g., metals coated with a layer of hydroxyapatite). The technique is generally used in osteosynthesis, joint replacements, orthopedic and traumatological bone reconstruction, spine surgery and maxillo-facial and odonthoiatric applications. Implants may be used to replace, at least partially, damaged bones, joints or teeth; or, they may be aid means used to fix bone parts or help these to keep the correct spatial relationship; in this second case the implants may be bone fixation plates (e.g., craniofacial, maxillo-facial, orthopedic, skeletal and the like), nails, screws, scaffolds and the like. The term “prosthesis” would be more appropriate for devices of the first kind, but as used in the present invention, it will be intended to mean both an actual prosthesis and any other aid means to be inserted in the human or animal body for the applications cited above.
Another technique adopted in orthopedics is the injection of biocompatible materials in damaged parts of bones, such as fractures or holes; the latter may result by the removal from bones of temporary implants, such as screws. The biocompatible material in this case has the function of temporarily replace the bone tissues, in order to maintain mechanical resistance, for the period necessary for such tissues to grow and fill the damaged area or space.
Bacterial infections due to implanted or injected biomaterials still represent a serious complication in orthopedic surgery. Many studies have documented the transfer of organisms from personnel in the operating theater to the patient during surgical interventions; see, e.g., Bather C. J. et al, “The effects of ‘in-use’ surgical handwashing on the pre- and postoperative fingertip flora during cardiothoracic and orthopaedic surgery”, Journal of Hospital Infection, (1995) 30, 283-293.
Acute or chronic osteomyelitic infections may also develop in many cases of osteosynthesis after bone fractures. In situations in which an inert foreign body is implanted into an already injured and weakened tissue, a competition develops for the colonization of the implant surfaces between bacteria (such as Staphylococcus Aureus, which has often been found in cases of contaminated bone fractures) and the cells of the immune system. However, bacteria have the advantages over immune system cells of faster reproductive processes and an extreme flexibility in adapting to the environment. Moreover, studies indicate that the procedures for implanting a prosthesis, and the presence of the prosthesis itself in the site of bone fracture, damage the response of the local immune system with the result that the number of bacteria required to cause an infection can fall by a factor of even 10,000 (Flückiger U. et al, “Factors influencing antimicrobial therapy of surface adhering microorganisms”, Recent Res. Devel. Antimicrob. Agents Chemother., (2000) 4, 165-175).
A standard implantation technique for prostheses and osteosynthesis consists of extensive removal of the necrotic and damaged tissue, cleaning of the cavity, implanting of a prosthesis and systemic parenteral prophylaxis with antibiotics. Similar procedures are adopted in case of injection of fluid biomaterials in fractures or bone cavities. The systemic release of antibiotics involves certain drawbacks such as systemic toxicity, reduced absorption into the ischemic or necrotic tissues and prolonged hospitalization to monitor drug levels and its effects. In cases in which bacterial colonization of the treated part is not efficiently avoided by systemic prophylaxis, a new surgical intervention (especially in case the replacement of the prosthesis is necessary), and an extension of the hospitalization period may be required, resulting in further discomfort for the patient.
In order to avoid these drawbacks, local antibiotic therapy has become an accepted and common alternative or adjunct to systemic antibiotic therapies, for prophylaxis and prevention of bacterial infections derived from orthopedic surgical interventions. Local antibiotic therapy offers various advantages over systemic therapy, including: a high active principle concentration at the infection site while eliminating systemic toxicity; a more thorough eradication of the infection; and the use of smaller drug doses which do not cause toxic effects.
For the aforesaid reasons, several researchers have proposed antibacterial materials with non-fouling properties, in particular for use as coatings of the orthopedic prostheses; such materials should preferably be capable to release an active principle immediately after the intervention and at least during the following 6 hours, preferably up to 48-72 hours, so as to cover the critical period of possible bacteria attack and proliferation in the intervention site.
Various carriers for local drug release have been developed and used, such as polymethylmethacrylate (PMMA) beds onto which the drug is loaded. These materials are however not reabsorbed and require subsequent intervention for their removal. Moreover the low porosity of the PMMA bed inhibits drug release by 25-50%, thus reducing the drug quantity released and increasing the risk of selection of bacterial mutants resistant to the active principle.
Biodegradable materials offer the advantages of bioreabsorption, which avoids subsequent intervention to remove them, reduces reactions induced by foreign bodies, and increases total release of the drug locally; besides, the kinetics of drug release from the matrix can be modulated by controlling the matrix degradation processes.
A known biodegradable and bioreabsorbable polymer is hyaluronic acid. Hyaluronic acid (also indicated as HA in the rest of the description) is a generic name for polysaccharides deriving from the polymerization of a repeating unit comprising D-glucuronic acid and N-acetyl-D-glucosamine. HA, in the forms naturally occurring in many animal tissues, may have a molecular weight (MW) ranging from about 5,000 to about 20 millions Dalton (Da), and the properties of a specific sample of the compound may vary depending on its actual MW. HA is a fundamental component of the extracellular matrix (ECM) and is essential for good operation of numerous body tissues such as connective or epithelial tissues, and in the inner ear fluids, in the vitreous humour of the eyes and also in the liquid essential for the joints (synovia). It is a highly biocompatible and biodegradable polymer with well known anti-adhesive and lubricity properties, the latter exploited in International patent application WO 2004/014303. However, HA as such is not suitable for injection or for the coating of prostheses, due to its rapid degradation by hyaluronidases, enzymes naturally occurring in the human and animal body; as a consequence of such rapid degradation, drug release over the required period can not be guaranteed. Furthermore, due to its high hydrophilicity, a coating produced with HA would not have sufficient mechanical stability when a prosthesis is implanted in the body, that is, an essentially water-based environment.
HA derivatives have been studied in view of various possible medical applications.
International patent application WO 2006/069578 discloses copolymers of HA with polymers of alpha hydroxyl acids or other polymers, for different uses in the cosmetic or medical field; this document does not cite the use of these HA-based copolymers for injection or the treatment of prostheses.
Patent EP 1773399 B1 discloses compositions obtained by the cross-linking of HA with a polyhydrazide; these compositions form hydrogels when contacted with water.
Patent application US 2004/0013626 A1 discloses nanoparticles to be used as drug vectors, formed of a polymer obtained by grafting at least one molecule of a polysaccharide to a biodegradable polymer different from the polysaccharide, preferably a polyester.
The paper “New amphiphilic lactic acid oligomer-hyaluronan conjugates: synthesis and physicochemical characterization”, Pravata L. et al, Biomacromolecules (2008) 9, 340-348, describes a HA derivative produced by grafting lactic acid oligomers (OLA), of average molecular weight around 500 Da, to hydroxyl radicals of the acid. These HA-OLA derivatives show lower hydrophilicity than HA and modified rheological properties compared to the same, making them more stable in an aqueous ambient, while maintaining good biodegradability and bioreabsorption characteristics.
The paper “New graft copolymers of hyaluronic acid and polylactic acid: synthesis and characterization”, Palumbo F. S. et al, Carbohydrate Polymers (2006) 66, 379-385, describes HA derivatives obtained by grafting poly-lactic acid (also abbreviated PLA in the rest of the description) to a HA of average MW of 266,000 Da with two different substitution degrees, in the first case a ratio PLA chains to HA repeating units of 1.5%, in the second case a substitution degree of 7.8%; the first compound is still rather hydrophilic, while the second is more hydrophobic and gives rise to gel-like dispersions in water. This paper indicates some possible applications of the disclosed graft copolymers in the biomedical field, such as the use of their aqueous solutions to reduce adhesion after abdominal surgery, in ophthalmic procedures and for the lubrication of joints, but no hint is given to possible uses in orthopedic implants.
The paper “Synthesis of novel graft copolymers of hyaluronan, polyethyleneglycol and polylactic acid”, Pitarresi G. et al, Macromolecules an Indian Journal, Vol. 3, Issue 2, August 2007, 53-56 describes HA derivatives obtained by grafting onto the HA chain both PLA and polyethylene glycol (abbreviated PEG), showing that these latter are less hydrophobic than compounds obtained by HA and PLA alone.
International patent application WO 2005/032417 discloses a coating produced using a physical mixture of HA with one or more biocompatible polymers, among which PLA, and loaded with an antimicrobial agent; this document also discloses the use of said mixture to produce a dry film charged with the antimicrobial agent onto the surface of a prosthesis, for subsequent implant. Prostheses coatings produced according to this document however suffer of at least two drawbacks: first, the antimicrobial agent, e.g. an antibiotic, has a limited lifetime, so it may not be completely efficient at the time of implant; second, this method does not allow to tailor the prosthesis coating to the specific requirements of the different cases, for instance, known intolerances of a patient to a given antibiotic, or the need to adopt a particular antibiotic, or a specific level of dosage of the same, in a specific situation.
Finally, patent application EP 1666518 A1 discloses drug carriers derived from a HA modification product, in which polyester chains (selected from polylactic acid, polyglycolic acid, and lactic acid-glycolic acid copolymers) are grafted onto the base HA chain. As stated in this document, and shown in all the formulas shown therein, the grafting of the polyester to the HA chain occurs by bonding, either directly or through di-amino or di-hidrazide spacers, to the carboxilic groups present on the glucuronic acid moieties of HA. This way, at least part the carboxilic groups of HA are transformed into amide groups; as the free carboxilic groups are responsible of the hydrophilicity of HA, the modification proposed in this document leads to a reduction of said hydrophilicity; in fact, the modified HA chains of EP 1666518 A1 exhibit a tendency to coil on themselves, making these products suitable for the production of micro- or nanospheres used as injectable drug carriers according to an aspect of the invention disclosed in the cited document. Besides, the compositions disclosed in this document are aimed and tailored to the sustained release of the drug, during a period longer than several days (see paragraph [0007] of the document), but this feature is not desirable in the specific field of orthopedics.
There is thus a need in the field for improved antibacterial materials for use in orthopedic surgery, not suffering the drawbacks of the prior art.